Amino acid analogs which can be incorporated into medicinally important synthetic peptides (or cyclic peptides) as replacements for natural amino acids, are known to impart favorable qualities on such peptides. For example, peptides containing unnatural amino acids can specifically inhibit proteases or peptidases, and/or may show enhanced receptor agonism or antagonism, when compared to their natural counterparts. Such modified peptides are useful as pharmaceutical agents.
Allen and Wade, Int. J. Peptide Protein Res., 32:89-97 (1988) demonstrated that a somatostatin analogue containing D-amino acids at or surrounding the scissile Lys-Thr bond rendered the analogue stable to attack by trypsin. These authors also report that modifying the side chain length of the target lys by substituting ornithine therefor inhibited proteolysis. Enhanced biological activity was demonstrated by Brady et al., J. Org. Chem., 52:764-769 (1987) wherein a highly potent cyclic hexapeptide somatostatin analogue was produced which contained both a D-amino acid and an N-methylated amino acid. Similarly, substitution of N-methylglycine (Sar) and N-methylalanine for proline as well as replacing arginine with its D-sterioisomer was shown to specifically increase antidiuretic potency in Arg-vasopressins (Zbigniew et al., J. Med. chem., 29:96-99 (1987). Others have measured the biological activity of bradykinin analogues where the arginine residues were modified by increasing or decreasing side chain length and by replacing the guanidino group with acetamidino and N-methylguanido groups (Pinker et al., J. Chem. Soc. Perkin Trans. I, 220-228 (1976). None of these authors, however, provide an analogue in which the conformation around the .alpha.-carbon can be simultaneously altered along with the side chain length, functionality, and spacial orientation.
Certain proline derivatives containing a sterically restricted amino side chain have been reported to interact via ionic or hydrogen bonds with certain polar residues of hemoglobin S (Hbs) and thereby inhibit hemoglobin polymeriation characteristic of sickle cell anemia, (Abraham et al., J. Med. Chem., 26:549-554 (1983)). These authors speculate that two other .gamma.-amino proline derivatives namely (4S)-1-butyryl-4-[(carboxymethyl)amino]-L-proline and its 1-benzoyl analogue containing a salicylate leaving group could covalently attach the .gamma.-amino prolyl derivative to the .epsilon.-amino of Lys 132. These stereo specific "cis" isomers were designed to bond with specific residues within a trapezoidol region between donor and acceptor HbS molecules and do not have the requisite side chain length to mimic arginin, ornithine or lysine.
Amino acid analogues suitable for replacement of arginine in bradykinin are described by Moore et al., J. Chem. Soc. Perkins Trans. I, 2025-2030 (1977). These authors report replacing the terminal Arg residues with, inter alia, p-guanidinophenyl-L-alanine. Compounds of this type do not posses the necessary conformational rigidity of the guanidino group provided to orient the side chain into specific regions of space.
Adams et al., U.S. Pat. No. 4,857,508, disclose arginine analogues in platelet-aggregation inhibitor peptide derivatives having the sequence X-Gly-Aso-Y where X is the arginine analogue, and is represented by H.sub.2 NC(NH)NH-(CH.sub.2).sub.n --CH(Z)COOH, where Z is H, NH.sub.2 or NH-Acyl and n ranges from 1-4. These arginine analogues, however, do not provide the requisite conformational rigidity around the .alpha.-carbon to restrict the guanidino group to particular spacial areas relative to the peptide backbone.
It can be seen from the foregoing that basic amino acid residues are important constituents of native and synthetic peptides but that adequate analogues of these amino acids are not available to fully explore the effect of amino acid side chain conformation on protein-protein or protein-peptide interaction. Accordingly, a need exists for a dibasic amino acid analogue having the proper size and conformational constraints to direct the basic side chain into specific regions of space relative to the peptide backbone. These analogs can mimic the bound state of the native peptide.